ABSTRACT
Repercussions of cisapride-induced blocking effects on repolarisation of K(+) channels in open and inactivated states investigated in rabbit ventricular myocardium during rest and under stimulation were compared with effects of K(+)-blocking drugs (4-aminopyridine, dofetilide, terikalant). Major lengthening in the first postrest action potential indicates affinity for closed channels. Gradual lengthening during stimulation implies affinity for open channels. Four (control, add-in, steady-state, washout) 20-min rest periods were alternated with regular stimulation (0.5 Hz). Each drug was added during add-in and steady-state periods. Similarly to dofetilide (10 nM) and terikalant (0.3 microM), cisapride (1 microM) increasingly lengthened action potentials during stimulation, whereas 4-aminopyridine (1 mM) prolonged mostly the first postrest action potential. Our results indicate that cisapride induced use-dependent lengthening of repolarisation, compatible with an affinity for open K(+) channels. We also found that in isolated rabbit ventricular myocytes, cisapride (1-10 microM) decreased the inward rectifier K(+) current, an effect contributing to the proarrhythmic potential.
Subject(s)
Action Potentials/drug effects , Cisapride/pharmacology , Heart Ventricles/drug effects , 4-Aminopyridine/pharmacology , Animals , Anti-Arrhythmia Agents/pharmacology , Chromans/pharmacology , Dose-Response Relationship, Drug , Electric Stimulation , In Vitro Techniques , Male , Phenethylamines/pharmacology , Piperidines/pharmacology , Rabbits , Sulfonamides/pharmacology , Time Factors , Ventricular FunctionABSTRACT
Sparfloxacin, a fluoroquinolone antibacterial, has been reported to prolong cardiac repolarization in some patients. In this study, we have investigated the in vitro cardiac electrophysiological effects of two other fluoroquinolones, levofloxacin and ofloxacin, and compared them with those exerted by sparfloxacin. Cardiac action potentials have been recorded from rabbit Purkinje fibers using conventional glass microelectrodes. The influence of a sudden decrease in stimulation rate on repolarization is examined. It is found that ofloxacin and levofloxacin (1-100 microM) do not alter the action potential parameters even at a concentration as high as 100 microM. The stimulation rate is without effect on repolarization. On the contrary, sparfloxacin (1-100 microM) lengthens concentration-dependently the duration of action potential, this effect being significant from the concentration of 10 microM. A non significant decrease in maximal rate of rise of phase 0 depolarization was observed at the concentration of 100 microM. Under low stimulation rate, the sparfloxacin-induced prolonging effect was magnified and early afterdepolarizations occurred in one of seven fibers from the concentration of 30 microM and in four other fibers at the concentration of 100 microM. These results suggest that levofloxacin and ofloxacin had no effect on cardiac cellular electrophysiology whereas sparfloxacin exerts pure class III electrophysiological effects, which can explain the prolongation of QT interval observed clinically in some patients and might become arrhythmogenic in the presence of other predisposing factors.
Subject(s)
Anti-Infective Agents/pharmacology , Fluoroquinolones , Levofloxacin , Ofloxacin/pharmacology , Purkinje Fibers/drug effects , Quinolones/pharmacology , Action Potentials/drug effects , Animals , Dose-Response Relationship, Drug , Female , In Vitro Techniques , Male , Purkinje Fibers/physiology , Rabbits , StereoisomerismABSTRACT
Cisapride, a gastrointestinal prokinetic agent, has been associated with cases of Torsades de Pointes but its effects on the cardiac action potential have not been described. We investigated its electrophysiological effects on rabbit isolated Purkinje fibres. The results demonstrated that cisapride (0.01-10 microM) lengthened concentration-dependently the action potential duration without modifying other parameters and induced early after depolarizations and subsequent triggered activity. This typical class III antiarrhythmic effect, that showed "reverse" rate-dependence and was reduced by increasing external K concentration, can account for clinical arrhythmogenesis.
Subject(s)
Anti-Arrhythmia Agents/pharmacology , Piperidines/pharmacology , Purkinje Fibers/drug effects , Action Potentials/drug effects , Animals , Arrhythmias, Cardiac/physiopathology , Cisapride , Electrophysiology , Heart/drug effects , Potassium/pharmacology , Purkinje Fibers/physiopathology , Rabbits , Torsades de Pointes/physiopathologyABSTRACT
Astemizole is a potent histamine H1-antagonist that has been associated with cases of life-threatening cardiac arrhythmias, including torsade de pointes and atrioventricular (AV) block. However, its effects on cardiac action potential (AP) has not been described. We examined the electrophysiological effects of astemizole on rabbit Purkinje fibers using conventional glass microelectrodes in parallel with the effects of the widely used histamine H2-antagonist cimetidine, selected because it has no known cardiac arrhythmic toxicity. Astemizole (0.01-3 microM) exerted a concentration-dependent prolonging effect on final repolarization that did not reach steady state after 3 h of exposure. This effect was more pronounced at low stimulation frequency and was less marked at high stimulation frequency. In addition, early afterdepolarizations (EADs) occurred in one third of the fibers. Increasing extracellular concentration of KCl (2.7-5.4 mM) or MgCl2 (1-5 mM) suppressed EADs and reversed the prolonging effect that was conversely exaggerated by decreasing KCl (4-2.7 mM) or MgCl2 (1-0.5 mM) concentration. At higher concentrations (3-30 microM), astemizole induced an increasing depressant effect on the maximal rate of depolarization (Vmax) that became more pronounced with high stimulation frequency. All parameters were strongly depressed at 10 microM astemizole, leading to cellular inexcitability in 5 of 12 fibers when exposed to 30 microM astemizole. In comparison, cimetidine induced minor changes on AP characteristics, i.e., a prolongation in plateau duration at high (30-100 microM) concentrations. These results provide evidence that astemizole exerts quinidine-like effects on cardiac APs that are compatible with the occurrence of the clinically observed arrhythmias.
Subject(s)
Arrhythmias, Cardiac/chemically induced , Astemizole/pharmacology , Histamine H1 Antagonists/pharmacology , Purkinje Fibers/drug effects , Action Potentials/drug effects , Animals , Astemizole/toxicity , Dose-Response Relationship, Drug , In Vitro Techniques , Magnesium Chloride/pharmacology , Potassium Chloride/pharmacology , Purkinje Fibers/physiology , Rabbits , Torsades de Pointes/chemically inducedABSTRACT
Vaughan-Williams class III antiarrhythmic agents act mainly by prolonging the duration of the cardiac action potential and, thus, the refractory period. This effect may be obtained: 1) by increasing the inward sodium or calcium currents, which may lead to an intracellular calcium overload and induce a very proarrhythmic situation, or 2) by decreasing the outward potassium currents, the objective of the new class III antiarrhythmic drugs under development. They selectively block one or several potassium channels regulated by the membrane potential (transient outward current Ito, delayed rectifying current IK and rectifying inward current IK1). Under physiological conditions the blockade of potassium channels regulated by a ligand (for example, ATP-dependent) does not lead to a class III effect. Prolongation of ventricular repolarisation is accompanied by a slowing of the heart rate and a positive inotropic effect. It is attenuated by rapid rhythms and amplified by slow rhythms: this is the reverse frequency-dependent phenomenon. However, normal frequency dependence (or "use-dependence") has been reported with the ionic channel, this paradox apparently being related to the complexity of the relations between the relative contributions of the ionic currents of repolarisation and their modulation by the heart rate. The class III effect confers a proarrhythmic potential and may lead to torsades de pointes, favorised by bradycardia, hypokalaemia and hypomagnesaemia. Experimentally, it favorises early after depolarisations which are presumed to be the cellular trigger event. The comprehension of factors influencing the antiarrhythmic and proarrhythmic class III effects has led to the establishment of a pharmacological profile of the "ideal" drug conferring the least proarrhythmic risk and the best efficacy.
Subject(s)
Anti-Arrhythmia Agents/pharmacology , Myocardium/pathology , Action Potentials/drug effects , Animals , Anti-Arrhythmia Agents/classification , Depression, Chemical , Humans , Ion Channel Gating/drug effects , Stimulation, ChemicalABSTRACT
We have compared the viability criteria of muscle bundles used in the in vitro contracture test for susceptibility to malignant hyperthermia (MH) in a group of 28 patients with various neuromuscular diseases (NMD) and 93 MH-related family patients. In the patients with NMD, this standard test gave one positive, six equivocal and 21 negative results. Compared with MH-related family patients, muscle bundles used had significantly smaller resting membrane potentials and smaller predrug twitch tension amplitudes. Some results from the group with NMD were obtained with muscles which were damaged, more rapidly deteriorating, non-standard or both, and should not be taken to indicate that the patients have the genetic trait for MH. The in vitro contracture test is not always relevant for myopathic muscle (especially dystrophic muscle) and this could explain the lack of specificity for MH.
Subject(s)
Malignant Hyperthermia/diagnosis , Muscles/physiopathology , Neuromuscular Diseases/physiopathology , Caffeine/pharmacology , Disease Susceptibility , Halothane/pharmacology , Humans , In Vitro Techniques , Malignant Hyperthermia/physiopathology , Membrane Potentials/physiology , Muscle Contraction/drug effectsABSTRACT
Cardiac arrhythmias and sudden death have been associated with both therapeutic and toxic doses of a number of cardiotropic and non-cardiac drugs. Generally the drug-induced electrocardiographic (ECG) alterations have been well described, whereas corresponding cellular electrophysiological effects are poorly documented or lacking. Taking into account the recent advances in the understanding of the mechanisms underlying arrhythmias and antiarrhythmic effects, suitable relationships can be established between ECG alterations and drug effects on cardiac action potential. Thus, a decrease in maximal upstroke velocity (Vmax) and membrane depolarisation leading to cellular inexcitability may slow conduction, prolong QRS interval duration and result in incessant wide QRS ventricular tachycardia. On the other hand, lengthening of the repolarisation phase and early afterdepolarisations (EADs) have been proposed as a mechanism for prolonged QT interval and subsequent Torsades de Pointes. A representative study aimed at detecting the arrthymogenic potentiality of a drug is given, by examining carefully the concentration- and frequency-dependent effects of four neuroleptics (sultopride, droperidol, thioridazine and clozapine) on Purkinje fibers and comparing them with the reported iatrogenic arrhythmias. The results showed that 10 to 100 microM sultopride and 0.01 to 1 microM droperidol exerted "pure" class III effects. In addition, higher concentrations (3 to 30 microM) of droperidol reversed the prolonging effect on repolarisation concomitantly with a dose- and frequency-dependent decrease in Vmax, action potential amplitude and resting membrane potential (class I effects) resulting in cellular inexcitability at 30 microM. Similar class I effects were induced by thioridazine and clozapine concomitantly with a slight prolonging effect on final repolarisation (class Ia effects). In the presence of sultopride (30 and 100 microM) and droperidol (0.3 to 3 microM), EADs developed at plateau level. Their incidence, amplitude and number were influenced by extracellular K or Mg concentration, stimulation frequency, modification of Ca entry (by nifedipine or isoproterenol). These experimental results fit well with clinical data although they need further development to precise underlying ionic mechanisms. Therefore, in vitro studies should be considered before clinical prospects for future drug development.
Subject(s)
Arrhythmias, Cardiac/chemically induced , Animals , Arrhythmias, Cardiac/physiopathology , Electrocardiography/drug effects , Electrophysiology/methods , Humans , Iatrogenic Disease , In Vitro TechniquesABSTRACT
This study was designed to clarify discrepancies concerning the effects of droperidol on cardiac repolarization. Myocardial electrical activity was recorded by using microelectrode technique in rabbit Purkinje fibers and guinea pig ventricular muscle. In Purkinje fibers stimulated at 60 pulses/min, low concentrations (0.01-0.3 microM) of droperidol increased in a dose-dependent fashion action potential duration (APD) without altering the other parameters. At 1 and 3 microM, droperidol led to the reversal of the prolonging effect. The highest concentrations used (10 and 30 microM), produced shortening in APD at 50% repolarization concomitantly with a significant decrease in Vmax, action potential amplitude and resting membrane potential. Inexcitability occurred in 4 of 15 preparations exposed to 30 microM. In 8 of 15 Purkinje fibers, the prolonging effect induced by low concentrations was so important that APD exceeded the 1000-msec period of basal stimulation and early afterdepolarizations (EADs) and triggered activity developed. In guinea pig ventricular muscle, these effects were notably less pronounced. Prolongation of action potential showed a reverse use-dependence (i.e., much greater at the lowest stimulation frequencies), whereas Vmax depression was use-dependent. Decreasing extracellular K concentration from 4.0 to 2.7 mM enhanced the incidence of EADs in Purkinje fibers, whereas elevating the K concentration from 2.7 to 5.4 mM abolished them completely and shortened drastically APD. EADs were also eliminated by increasing magnesium concentration from 1 to 5 mM. Addition of isoproterenol favored EADs, whereas these were suppressed at plateau level by exposure to 0.3 microM nifedipine. The results indicate that in rabbit Purkinje fibers, droperidol exerts a dual effect on repolarization, prolongation with low concentrations with development of EADs and subsequent triggered activity. These abnormalities were suppressed at high concentrations concomitantly with a marked depression of other characteristics. These observations suggest multiple ionic channel activities and further studies are required to precise the underlying mechanisms at channel level.
Subject(s)
Droperidol/pharmacology , Purkinje Fibers/drug effects , Action Potentials/drug effects , Animals , Dose-Response Relationship, Drug , In Vitro Techniques , Male , Purkinje Fibers/physiology , RabbitsABSTRACT
BACKGROUND: The response to contracture tests may depend upon the relative proportion of muscle fiber types within the muscle specimen. To determine whether a difference in fiber-type caffeine sensitivities exists between malignant hyperthermia susceptible (MHS) and malignant hyperthermia-nonsusceptible (MHN) skeletal muscle, we compared the fiber-type caffeine sensitivities in chemically skinned muscle fibers dissected from vastus lateralis muscle from 15 MHS and 16 MHN patients. METHODS: Muscle fiber type was determined in each fiber by the difference in strontium-induced tension measurements and in 36 fibers, after contracture testing, by ATPase enzyme histochemistry. Caffeine sensitivity was defined as the threshold concentration inducing more than 10% of the maximal tension obtained with a calcium 1.6 x 10(-2) mM solution. RESULTS: Significant difference in the mean (+/- SD) caffeine sensitivity was found between type I MHS fibers (2.63 +/- 0.85 mM) versus type II MHS fibers (3.47 +/- 1.2 mM) and between type I MHN fibers (5.89 +/- 1.8 mM) versus type II MHN fibers (10.46 +/- 2.6 mM). The mean (+/- SD) caffeine sensitivities for a given muscle fiber type (I or II) were different between groups of MHS and MHN patients. Both type I and II MHS fibers had significantly lower caffeine sensitivities, and this increase in caffeine sensitivity was significantly smaller in type I than in type II fiber. CONCLUSIONS: The current study indicates that a truly MHS patient cannot have a false-negative result solely related to abnormal type II fibers contained in a given muscle strip. Although the occurrence of a very high proportion of type I fibers in MHN human muscle could result in a false-positive contracture outcome, such an occurrence is expected to be rare.
Subject(s)
Caffeine/pharmacology , Malignant Hyperthermia/physiopathology , Muscles/drug effects , Disease Susceptibility/physiopathology , Humans , In Vitro Techniques , Muscles/physiologyABSTRACT
Isoflurane has a lesser ability than halothane to induce contracture in malignant hyperthermia (MH) muscle in vitro. This does not necessarily imply that isoflurane is not as potent an MH trigger as halothane in vivo. A hypothesis was tested that in vitro treatment with Bay K 8644, an activator of both the dihydropyridine receptors as well as the sodium channels of the T-tubules, potentiates isoflurane-induced MH-susceptible skeletal muscle contracture. In addition to the usual halothane-caffeine test, other muscle bundles were exposed to 10 microM Bay K 8644-halothane and equipotent anesthetic concentrations (expressed in multiple minimum alveolar concentration [MAC]) of isoflurane either alone or combined with Bay K 8644. In 14 MH-susceptible muscle bundles, the mean maximum contracture induced by 2 MAC isoflurane was 0.20 +/- 0.22 g (mean +/- SD), and this value was significantly less than that obtained with 2 MAC halothane (0.68 +/- 0.40 g). Bay K 8644 did not induce muscle contracture on its own but consistently enhanced both the 0.5 MAC isoflurane and halothane to the same maximal isometric tension (1.09 +/- 0.35 g and 1.11 +/- 0.37 g, respectively). Such an effect was not observed in the MH-nonsusceptible group. Under the conditions of this in vitro study, 0.5 MAC isoflurane appears to be as potent as halothane in inducing muscle contracture in skeletal muscle bundles from individuals susceptible to MH.
Subject(s)
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester/pharmacology , Halothane/pharmacology , Isoflurane/pharmacology , Malignant Hyperthermia , Muscle Contraction/drug effects , Calcium Channel Blockers/pharmacology , Calcium Channels , Disease Susceptibility , Dose-Response Relationship, Drug , Drug Synergism , Humans , Receptors, Nicotinic/drug effectsABSTRACT
To evaluate whether the hydroxylated metabolites of quinidine (Q) and hydroquinidine (HQ): hydroxy-3S-quinidine (OH-Q) and hydroxy-3S-hydroquinidine (OH-HQ), exert electrophysiologic effects and participate in the therapeutic action of the parent drugs, we examined and compared the effects of the metabolites and the parent drugs on the electrical activity of guinea pig ventricular cells recorded by standard microelectrode technique. In addition, we investigated the potential arrhythmogenic properties of these compounds in rabbit Purkinje fibers in low K+ (2.7 mM) Tyrode's solution. The concentration [C]-, frequency-, and voltage-dependent effects of the drugs were investigated. Maximum upstroke velocity of phase 0 (Vmax) was [C]-dependently depressed by both OH-Q and OH-HQ but at a lesser degree than with Q and HQ, respectively: at the [C] of 50 microM, Vmax depression attained 26.7 +/- 2.6% with OH-Q versus 45.9 +/- 1.6% with Q and 32.3 +/- 1.9% with OH-HQ versus 54.6 +/- 1.4% with HQ. This effect was frequency and voltage dependent without significant differences between the four compounds. In the presence of equipotent [C], recovery kinetics of Vmax was significantly slower with metabolites than with respective parent drugs. In contrast, the effects of metabolites on action potential duration at 90% of repolarization (APD90) and effective refractory period (ERP) differed from those observed with parent drugs. With metabolites, APD90 and ERP were increased in a [C]-dependent manner, whereas the Q- and HQ-induced lengthening in APD90 and ERP was observed only at low concentration and low frequency. In addition, the OH-Q- and OH-HQ-induced APD90 lengthening was not altered by increasing pacing rate. In rabbit Purkinje fibers, increase in cycle length and prolonged exposure to either metabolites or parent drug caused early afterdepolarizations (EADs) and triggered activity. With all drugs tested, EADs arose more frequently at the plateau level than at the final repolarization of AP, but the incidence of EADs appeared to be much lower with metabolites than with parent drugs. The present results demonstrate that OH-Q and OH-HQ exert qualitatively similar but quantitatively less potent depressant effects on Vmax than Q and HQ, respectively, but differ in the lengthening effect on APD. We suggest that metabolites may participate in class I antiarrhythmic action of their respective parent drug and contribute to their arrhythmogenicity.
Subject(s)
Anti-Arrhythmia Agents/pharmacology , Heart/drug effects , Quinidine/analogs & derivatives , Quinidine/pharmacology , Action Potentials/drug effects , Animals , Electrophysiology , Guinea Pigs , Heart/physiology , Heart Ventricles/cytology , Heart Ventricles/drug effects , In Vitro Techniques , Kinetics , Potassium/pharmacology , Purkinje Fibers/drug effects , Purkinje Fibers/physiology , Quinidine/metabolism , RabbitsABSTRACT
Overdose cardiac effects of imipramine are due to fast Na channel blockade and are clinically reversed by administration of sodium lactate which induces alkalosis (about pH 7.50) and hypernatremia (about 8 mM). The mechanisms of this beneficial effect of Na lactate were explored in vitro on guinea-pig ventricular myocardium using the microelectrode technique. The time-course effects of the clinically relevant concentration of 10 microM imipramine on action potential characteristics were examined at pH 7.20 and pH 7.50. To test whether alkalinisation per se is important or whether an increase in Na concentration plays a major role in the reversal effect, preparations were exposed to increasing concentrations (1, 3, 10, 30, 100 mM) of either Na lactate, bicarbonate or chloride in the absence or in the presence of 10 microM imipramine at pH 7.50. The influence of elevating osmolality was evaluated with equivalent concentrations of sucrose. Imipramine alone significantly depressed Vmax and shortened action potential duration at all phases of repolarisation. All three high sodium solutions reversed imipramine effects. However the reversal effect was already obvious with 10 mM Na lactate and 10 mM NaHCO3 but not 10 mM NaCl. Osmolality did not reverse the imipramine-induced Vmax depression. The results suggest that at the clinically relevant 10 mM concentration, sodium lactate and bicarbonate may displace imipramine from its receptor site on the Na channel by causing alkalosis at the membrane level without profoundly affecting the driving force of the Na current, whereas at the upper concentrations, the increase in Na ion concentrations is predominantly involved in the reversal of imipramine effects.
Subject(s)
Action Potentials/drug effects , Imipramine/antagonists & inhibitors , Lactates/pharmacology , Myocardium/chemistry , Animals , Bicarbonates/pharmacology , Female , Guinea Pigs , Heart Ventricles/drug effects , Hydrogen-Ion Concentration , Imipramine/pharmacology , Lactic Acid , Male , Osmolar Concentration , Sodium/pharmacology , Sodium Bicarbonate , Sodium Chloride/pharmacologyABSTRACT
In 22 patients susceptible to and 34 patients not susceptible to malignant hyperthermia, we examined which muscle conditions may influence the degree of sensitivity of skeletal muscle to the in vitro caffeine contracture test: predrug resting membrane potential, predrug twitch tension, and maximum contracture induced by 32 mM caffeine in two caffeine tests performed respectively at 30 and 75 min after biopsy. No differences in the measured variables were observed between the first and the second caffeine tests in the 34 patients susceptible to malignant hyperthermia. The first caffeine test was found to be positive in all of the 22 patients susceptible to malignant hyperthermia. However, in eight patients, the second caffeine test was negative and the muscle fibers were found to be significantly depolarized. Resting membrane potential was -73.4 +/- 7.9 mV before the first caffeine test and -65.8 +/- 8.8 mV before the second test. We suggest that when time-induced partial depolarization of malignant hyperthermia-susceptible fibers occurs, fibers may become less sensitive to caffeine.
Subject(s)
Caffeine/pharmacology , Malignant Hyperthermia/metabolism , Membrane Potentials/drug effects , Muscles/drug effects , Electric Stimulation , Halothane/pharmacology , Humans , Malignant Hyperthermia/diagnosis , Muscle Contraction/drug effectsABSTRACT
The electrophysiological effects of oxidized low density lipoproteins (ox-LDLs) have been studied in rabbit Purkinje fibers using standard microelectrode techniques, in comparison with native LDLs (n-LDLs) and lysophosphatidylcholine (LPC). At the concentration of 100 micrograms protein/ml, ox-LDL but never n-LDL induced the abrupt occurrence of abnormal electrical activities during the basic stimulation of 1 Hz (6/13 fibers) and the development of either early afterdepolarizations (6/13 fibers) or abnormal automaticity (4/13 fibers) at low frequencies (0.1 and 0.03 Hz). Short trains of rapid stimulation (2, 3, 4 and 5 Hz) did not trigger delayed afterdepolarizations. However, early afterhyperpolarizations were commonly seen after each action potential. 30 microM LPC caused quite similar electrophysiological derangements. The results suggest that ox-LDLs may exert arrhythmogenic effects partly explained by their LPC content.
Subject(s)
Heart Rate/drug effects , Lipoproteins, LDL/pharmacology , Purkinje Fibers/physiology , Action Potentials/drug effects , Animals , Electric Stimulation , Heart Ventricles , Humans , In Vitro Techniques , Lipoproteins, LDL/blood , Lipoproteins, LDL/isolation & purification , Male , Membrane Potentials/drug effects , Oxidation-Reduction , Purkinje Fibers/drug effects , RabbitsABSTRACT
The purpose of this investigation was to determine if alteration in the function of the dihydropyridine receptor may in turn modify halothane-induced contractures in muscle bundles from patients susceptible to malignant hyperthermia (MH). The effects of Ca(2+)-free Krebs Ringer (KR) solution, 5 microM verapamil, 5 microM nifedipine, and 10 microM of the Ca2+ agonist BAY K 8644 on halothane-induced contracture were therefore investigated. The halothane-induced contracture was prevented in the absence of extracellular Ca2+ and significantly reduced in the presence of verapamil or nifedipine. BAY K 8644 significantly enhanced the 0.5-, 1.0-, and 1.5-vol % halothane-induced contracture in MH-susceptible muscle bundles. When BAY K 8644 was dissolved in Ca(2+)-free KR solution, no contracture was observed in MH-susceptible muscle bundles. These results on cut MH-susceptible human muscle bundles support the hypothesis that halothane-induced contracture in MH can be modified by the binding of Ca2+ agonists or antagonists to the dihydropyridine receptor. The role of Ca2+ entry phenomena remains unclear, but the results suggest that extracellular Ca2+ is required to reprime or to bind to some sites of the dihydropyridine receptors.
Subject(s)
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester/pharmacology , Calcium Channel Blockers/metabolism , Halothane/pharmacology , Malignant Hyperthermia/physiopathology , Muscle Contraction/drug effects , Receptors, Nicotinic/metabolism , Biopsy , Calcium Channels , Disease Susceptibility , Humans , In Vitro Techniques , Isotonic Solutions/pharmacology , Muscles/chemistry , Nifedipine/pharmacology , Verapamil/pharmacologyABSTRACT
We have studied the effects of the calcium agonist BAY K 8644 on the in vitro halothane test in 10 malignant hyperthermia-susceptible (MHS), 12 MH "equivocal" to halothane (MHEh), 30 MH non-susceptible (MHN) and 10 control patients. BAY K 8644 potentiated the halothane-induced contracture in muscle strips from both MHS and MHEh patients. The drug produced a more obvious difference in contracture responses between the MHEh group compared with the MHN and control groups.
Subject(s)
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester , Malignant Hyperthermia/diagnosis , 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester/pharmacology , Caffeine/pharmacology , Disease Susceptibility , Drug Synergism , Halothane/pharmacology , Humans , In Vitro Techniques , Muscle Contraction/drug effectsABSTRACT
The effects of diltiazem (1 microM) and nifedipine (1 microM) were examined separately on the in vitro halothane tests for malignant hyperthermia (MH) susceptibility. Eighteen patients with MH susceptibility were diagnosed as MH-susceptible (MHS) according to the protocol of the European MH Group. In addition, halothane tests were carried out in the presence of either diltiazem (ten patients) or nifedipine (eight patients). These two calcium channel blockers significantly reduced the halothane contracture. Furthermore, in five of the ten MHS patients tested in the presence of diltiazem as well as in five of the eight MHS patients tested in the presence of nifedipine the halothane contracture test could be classified as negative. It is concluded that the presence of clinical concentrations of either diltiazem or nifedipine in the muscle bath affects the in vitro discrimination for MH susceptibility to halothane.
Subject(s)
Diltiazem/pharmacology , Halothane , Malignant Hyperthermia/physiopathology , Muscle Contraction/drug effects , Nifedipine/pharmacology , Depression, Chemical , Disease Susceptibility , Humans , In Vitro TechniquesABSTRACT
We examined the effects of verapamil on the in vitro caffeine and halothane tests for malignant hyperpyrexia (MH) susceptibility. Ten consecutive MH-susceptible patients were investigated according to the protocol of the European MH group. Additional tests were carried out in the presence of verapamil 10(-6) mol litre-1. In four of the 10 patients, the halothane contracture response following pretreatment with verapamil was classified as positive to halothane. In contrast, in nine of the 10 patients, contracture tests of muscle in the presence of verapamil were classified as negative to caffeine. It is advised that verapamil should be discontinued before performing a contracture test.
Subject(s)
Malignant Hyperthermia/diagnosis , Verapamil/pharmacology , Caffeine , Disease Susceptibility/diagnosis , False Negative Reactions , Halothane , Humans , In Vitro Techniques , Muscle Contraction/drug effects , Sensory Thresholds/drug effectsABSTRACT
The neuroleptic malignant syndrome (NMS) is an uncommon but dangerous complication of treatment with neuroleptic drugs. A primary defect in skeletal muscle has been suggested in view of similarities in the clinical presentations of NMS and anaesthetic-induced malignant hyperthermia (MH). The in vitro halothane-caffeine contracture tests are the most reliable method of identifying individuals susceptible to MH. The aim of this study was to define if a relationship exists between NMS and MH susceptibility. Hence, the in vitro halothane and caffeine contracture tests were performed on muscle tissue obtained from eight NMS, ten MH-susceptible and ten control patients. The results, which are expressed in accordance with the criteria of the European MH Group, defined the eight NMS subjects as MH non-susceptible. The response to halothane and caffeine exposure of skeletal muscle from NMS and control subjects was the same and significantly different from that of muscle from patients susceptible to MH. Furthermore, muscle from subjects in NMS and control group responded similarly to increasing concentrations of chlorpromazine. These results do not point towards an association between NMS and MH.
Subject(s)
Malignant Hyperthermia/physiopathology , Neuroleptic Malignant Syndrome/physiopathology , Adult , Caffeine , Chlorpromazine/pharmacology , Contracture/chemically induced , Disease Susceptibility , Female , Halothane , Humans , Male , Malignant Hyperthermia/complications , Middle Aged , Muscle Contraction/drug effects , Neuroleptic Malignant Syndrome/complicationsABSTRACT
Propafenone (Pf) is a class I antiarrhythmic drug that can be given both orally and intravenously. In order to examine whether its two major metabolites [5-hydroxypropafenone (5-OH-Pf) and N-depropylpropafenone (N-DP-Pf)] possess pharmacodynamical properties, we compared their electrophysiological effects to those of the parent drug on papillary muscle fibers from guinea pig ventricular myocardium. After baseline action potential and refractory period characteristics were measured at different pacing rates, the tissue preparations were superfused with either Pf, 5-OH-Pf, or N-DP-Pf at five different concentrations and electrophysiological characteristics were studied again. The maximal rate of depolarization (Vmax) was depressed by the three compounds only at the highest concentration, although the effect of N-DP-Pf was slightly less than the other two. Refractory periods were altered only by the highest concentration of 5-OH-Pf. Propafenone and N-DP-Pf exhibited equally slow on-set/off-set kinetics of the sodium channel block, whereas those of 5-OH-Pf were twice as long, which seems to suggest a slower rate of dissociation of the latter from the inactivated sodium channels. Thus, 5-OH-Pf and N-DP-Pf comply with the definition of the class IC antiarrhythmic drugs. The cumulative in vivo effects of the two metabolites and of the parent drug could have far reaching clinical implications, especially in the genetically predisposed extensive metabolizing subject.